The trend in internal fixation devices for repair of damaged bone is toward the use of resorbable, tissue compatible biopolymers. Biopolymers such as poly(glycolic acid) (PGA), poly(lactide) (PLA), and copolymers of lactic and glycolic acids, (poly(lactide-co-glycolide) or PLGA) have been used in the production of internal fixation devices, such as screws, pins, and rods to hold bone together following surgery, or to repair broken bones. Other polymers, such as poly(dioxanone) , have also been considered for use in the manufacture of surgical internal fixation devices. However, it has been observed that tissue response to resorbable implants fabricated from these biopolymers is not uniformly acceptable (Bostman, J. Bone and Joint Surg. 73, 148-153 (1991)).
The tissue response to biopolymer-based implants has been well documented. Late sterile inflammatory foreign body response (sterile abscess) has been reported in about 8% of fractures repaired with these polymers (Bostman, supra). In a randomized study of 56 open reduction and internal fixation of malleolar fractures of the ankle with metal ASIF screws and plates or with rods of PLGA, two cases of sterile inflammatory wound sinus were observed 3 to 4 months after the operation in the injuries fixed with the polymer rods (Rokkanen et al., Lancet 1, 1422-1425 (1985); Bostman et al., J. Bone and Joint Surg., 69-B(4), 615-619 (1987)). Other studies have also documented an inflammatory reaction following implantation of PGA or PLGA fixation devices. The fraction of patients suffering from this reaction ranges from 4.6 to 22.5% (Bostman et al., Clin. Orthop. 238, 195-203 (1989); Bostman et al., Internat. Orthop. 14, 1-8 (1990); Hirvensalo et al., Acta Orthop. Scandinavica, Supplementum 227, 78-79 (1988); Hoffman et al., Unfallchirurgie 92, 430-434 (1989); Partio et al., Acta Orthop. Scandinavica, Supplementum 237, 43-44 (1990); Bostman et al., Internat. Orthop. 14, 1-8 (1990)). The inflammatory reaction is not limited to poly(glycolide) polymers. Internal fixation devices made from poly(lactide) have also been observed to exhibit an inflammatory reaction. Eitenmuller et al. reports that 9 of 19 patients (47.7%) who had fractures of the ankle treated with absorbable plates and screws of poly(lactide) had an inflammatory response. (J. Eitenmuller, A. David, A. Pomoner, and G. Muhyr: xe2x80x9cDie Versorgung von Sprunggelenlzsfrakturen unter Verwendung von Platten und Schrauben aus resorbserbarem Polymermaterialxe2x80x9d, Read at Jahrestagung der Deutschen Gesellschaft fur Unfallheilkunde, Berlin, Nov. 22, 1989).
In vitro studies have been performed to monitor pH changes as well as weight loss and the appearance of lactic acid from screws fabricated from poly(lactide-co-glycolide) with a lactide:glycolide ratio of 85:15. (Vert et al., J. Controlled Release 16, 15-26 (1991)). An induction period of about ten weeks was observed before any significant change in media pH or weight loss occurred. This time period corresponds to the induction periods of seven to twenty weeks noted by clinicians. However, no attempt has been made to alleviate the source of inflammation.
The invention is a bioerodible, or resorbable, implantable material, and devices made therefrom, comprising a bioerodible polymer that produces acidic products or low molecular weight resorbable fragments upon hydrolytic degradation, and a neutralization or buffering compound included in sufficiently high concentration to buffer the acidic products and maintain the local pH within a desired range or to decrease the rate of pH change as the implantable material degrades. The buffer compound incorporated into the material of the invention acts to neutralize the acidic degradation products which cause inflammatory foreign body response upon degradation of the bioerodible polymer. Thus, the invention reduces the sterile abscess condition that occurs in the bioerodible implant materials of the prior art.
Materials made according to the invention may be used for internal fixation devices (IFDs) for, e.g., the repair, replacement or reconstruction of damaged bone in any area of the body. For example, screws, pins and rods according to the invention are useful to hold bones together following surgery or to repair broken bones. An interbody spinal fusion device according to the invention can be used for spine repair. Bone graft devices according to the invention can be used to repair or reconstruct defects caused by surgery, tumors, trauma, implant revisions and infections, and also for joint fusion. Void filler devices according to the invention can be placed in the void created by removal of, e.g., a cyst or infected bone, or from trauma. A space-filling internal fixation device according to the invention can be prepared either ex situ or in situ, e.g., in the form of a space-filling, solidifying foam. Furthermore, IFDs according to the invention are also useful, e.g., as stents to separate or maintain the shape of blood vessels, as sutures or fibrous devices for incision repair, or for any other use that may benefit from the combination of a bioerodible polymer with a neutralization or buffering compound into an implantable internal fixation device.
The bioerodible materials and methods of the invention include a bioerodible polymer that forms acidic products as it degrades. The bioerodible polymer undergoes hydrolysis in the body and generates acidic products that cause irritation, inflammation, and swelling (sterile abscess formation) in the treated area. To counteract this effect, a neutralization compound, or buffer, is included in the bioerodible material to neutralize the acidic degradation products, or control the rate of pH decline, and thereby reduce the sterile abscess reaction. The neutralization compound included in the bioerodible material of the invention maintains the pH surrounding the area of surgery at approximately neutrality (i.e., pH 7), or any other pH chosen by the surgeon. Preferably, the pH is maintained in the range of 6-8, and more preferably in the range of 6.8-7.4. Alternatively, the neutralization compound controls the rate of acid production as the bioerodible material degrades, thereby serving to control the rate of pH decrease.
According to the invention, the bioerodible material includes a bioerodible polymer that undergoes hydrolysis to produce acidic products when exposed to an aqueous medium. In one preferred embodiment, the polymer poly(lactide-co-glycolide) (H[xe2x80x94OCHRxe2x80x94COxe2x80x94]nOH, Rxe2x95x90H, CH3) (PLGA) is used. The PLGA polymers used according to the invention have a lactide to glycolide ratio in the range of 0:100% to 100:0%, inclusive, i.e., the PLGA polymer can consist of 100% lactide, 100% glycolide, or any combination of lactide and glycolide residues. These polymers have the property of degrading hydrolytically to form lactic and glycolic acids. In another preferred embodiment, the bioerodible polymer is poly(propylene fumarate) (H[xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94]nOH), which may be desirably crosslinked using vinyl monomers such as vinyl pyrrolidone (VP). An advantage of VP crosslinking of PPF is that the crosslinks terminate at hydrolytically labile fumarate ester bonds, making the crosslinked network hydrolytically degradable. Furthermore, the hydrolysis products are highly soluble. Other bioerodible polymers useful in the invention include polydioxanone, poly(xcex5-caprolactone); polyanhydrides; poly(ortho esters); copoly(ether-esters); polyamides; polylactones; and combinations thereof.
The neutralization or buffering compound included in the bioerodible material of the invention may be any salt, base, base-containing or base-generating material that is capable of reacting with the acidic products generated upon hydrolysis of the bioerodible polymer. Exemplary buffering materials that may be implemented according to the invention include the salts of inorganic acids, the salts of organic acids, or the salts of polymeric organic acids. Preferably, the calcium salts of weak acids are used, such as calcium phosphate, although calcium carbonates, calcium acetates, calcium citrates and calcium succinates may also be used.
Polymeric buffers may also be used as buffering compounds according to the invention. Suitable polymeric buffers preferably include basic groups which neutralize the acidic products generated upon hydrolysis of the bioerodible polymer. Such polymeric buffers include hydrolyzable polyamines, hydrolytically stable polymers, such as poly(N-vinyl carbazole), poly(N-vinyl pyrrolidone), poly(acrylic acid), poly(acrylamide), or a copolymer based on acrylic acid.
Another class of buffering compounds useful in the materials and methods of the invention are compounds which, on exposure to water, hydrolyze to form a base as one reaction product. The generated base is free to neutralize the acidic products produced upon hydrolysis of the bioerodible polymer. Compounds of this type include aryl or alkyl carbamic acids and imines. The base-generating compounds used according to the invention offer the advantage that the rate of hydrolysis of the base generator may be selected to correlate to the rate of hydrolysis of the bioerodible polymer.
Preferably, the buffering compound has an acid dissociation constant that is smaller than the acid dissociation constant of the acidic products generated upon hydrolysis of the bioerodible polymer. Alternatively, the buffering compound preferably has a hydrolysis constant that is greater than the hydrolysis constant of the acidic products.
Preferably, the buffering compound included in the material of the invention is only partially soluble in an aqueous medium. In general, buffers of lower solubility are preferred because buffer loss from the polymer by diffusion will be minimized (Gresser and Sanderson, xe2x80x9cBasis for Design of biodegradable Polymers for Sustained Release of Biologically Active Agentsxe2x80x9d in Biopolymeric Controlled Release Systems, Ch. 8, D. L. Wise, Ed., CRC Press, 1984).
In yet another embodiment, devices made from the bioerodible implantable material of the invention further include reinforcing fibers to enhance the structural properties thereof. These fibers may be made of polymeric material that is the same as or similar to the bioerodible material from which the device is made, from material that is the same as or similar to that of the neutralization compound or, alternatively, from another biocompatible polymer, which may be crosslinked with a suitable crosslinking agent to yield an interpenetrating network for increased strength and stability. In another alternative embodiment, the reinforcing fibers are incorporated into the device, e.g., during the molding process, being placed in the mold under tension and released after the process of molding is complete.
In another alternative embodiment, devices made from the bioerodible implantable material of the invention preferably include a biological growth factor, e.g., bone morphogenic protein, to enhance bone cell growth. The growth factor may simply be directly incorporated into the component formulation of a device. Alternatively, to protect the growth factor and to provide for controlled delivery, the biological growth factor may itself be compounded with a bioerodible, resorbable polymer in some of the many techniques available and prepared as a growth factor/polymer composite in pellet form, in small particle form or within the interstices or pores of a polymeric foam or low-density polymer. This polymer/growth factor composite may be incorporated directly into the component formulation or deposited into void spaces that have been created in the device.
Active bone cell material, e.g., periosteal cells or osteoblasts, may also be incorporated into a device, in order to facilitate bone cell growth. For example, the bone cells may first be incorporated into a biocompatible, bioerodible foam material and then deposited into void spaces of a device. In addition, a device made from the bioerodible implantable material of the invention may be prepared in such a manner as to exhibit a piezoelectric effect, to enhance bone wound healing.
The invention also includes methods of making a buffered bioerodible material for implantation into a surgical site. In one embodiment, the method according to the invention includes the steps of dissolving a bioerodible polymer in a solvent, and mixing a buffering compound with the dissolved bioerodible polymer, the buffering compound capable of buffering the acidic products within a desired pH range. The solvent is evaporated to produce a buffered bioerodible implantable material in film form. The resulting film may be further processed, for example, compacted under pressure, extruded through a die, injection molded, or shaped into a form useful for implantation.
In another embodiment, the method according to the invention includes mixing dry, solid bioerodible polymer particles of a specific size with dry, solid buffering compound particles of a specific size, and mixing the bioerodible polymer particles and the buffering compound particles in a desired proportion. This mixture may also be processed by, e.g., compacting, extrusion, injection molding, or shaping procedures.
In another embodiment, the method of the invention includes providing an open celled bioerodible foam polymer of controlled density and providing a buffer dissolved in a solvent wherein the foam polymer is not soluble in the solvent, such as described in U.S. Pat. No. 5,456,917 to Wise et al., the whole of which is incorporated by reference herein. The buffer is loaded into the foam polymer, and the loaded foam polymer is freeze dried to remove the solvent. The resulting loaded bioerodible polymer may be further ground into particles of a predetermined size, extruded through a die, or shaped into useful forms.
In another embodiment, the method of the invention includes providing a bioerodible polymer having a melting temperature and producing acidic products upon hydrolytic degradation, providing buffer particles comprising buffer material coated with a polymer having a melting temperature greater than the melting temperature of the bioerodible polymer. The bioerodible polymer is heated to a temperature between the melting temperatures of the bioerodible polymer and the coating polymer, and the heated bioerodible polymer is mixed with the coated buffer particles. The mixture is then cooled and processed into useful forms.
As used herein, the terms xe2x80x9cresorbablexe2x80x9d and xe2x80x9cbioresorbablexe2x80x9d are defined as the biologic elimination of the products of degradation by metabolism and/or excretion and the term xe2x80x9cbioerodiblexe2x80x9d is defined as the susceptibility of a biomaterial to degradation over time, usually months. The terms xe2x80x9cneutralization compoundxe2x80x9d or xe2x80x9cbufferxe2x80x9d are defined as any material that limits or moderates the rate of change of the pH in the implant and its near environment upon exposure to acid or base. The term xe2x80x9cacidic productsxe2x80x9d is defined herein as any product that generates an aqueous solution with a pH less than 7.